(1) Field of the Invention
During the study of limonene as a hand cleaner, the applicants found that fully oxygenated limonene is a fungicide. A review of the literature revealed that oxygenated limonene contains several oxidation products including: limonene-1,2-oxide limonene-8,9-oxide, 1-menthene-9-al, .alpha.-2,8-p-menthadiene-1-ol .beta.-2,8-p-menthadiene-1-ol, dihydrocarvone, .alpha.-cymenol, carvone, cis-carveol and trans-carveol, as was outlined by Bain in U.S. Pat. Nos. 2,863,882 and 3,014,047. Blumann listed the compounds formed by the auto-oxidation of limonene in Chemical Abstracts. Volume 63, 1965, on page 1819, which included cis and trans-carveol, trans-p-menth-8-ene-1,2-diol, limonene 1,2-epoxide, limonene 8,9-epoxide, cis and trans-p-mentha-2,8-dien-1-o1, and perillyl alcohol. The applicants found that carveol is a principal anti-yeast and anti-fungal compound generated by the oxidation of limonene and that in effective concentrations carveol kills yeast and in fungicidal concentrations carveol kills fungi.
Carveol is a monocyclic monoterpene with the following chemical formula: ##STR1##
Carveol is an oil with a terpenic aroma. It is insoluble in water and glycerine. Carveol is soluble in alcohol and is miscible in corn oil, olive oil, and soybean oil. Carveol has been used as a bactericide but heretofore, it has never been shown to kill yeast or fungi.
Carveol can be produced by the oxidation of limonene as was outlined by Bain in U.S Pat. Nos. 2,863,882 and 3,014,047. Carveol can be obtained from .alpha.-pinene, and .beta.-pinene by the Cu+ catalyzed oxidation with benzoyl peroxide as was demonstrated by Walling et. al. in Canadian Patent 981,695. Mestroni et al showed that carveol can be produced by the catalyzed conversion of carvone and dihydrocarvone to carveol as was outlined in German Offen 3,008,671 in the Chemical Abstracts, Volume 93, 1980, page 807. Bain, in U.S. Pat. No. 2,803,647 showed his method of producing carveol and dihydrocarveol and their esters. In the Indian Journal of Chemistry, 1975, 13(11), pages 1239-40, Mistra outlined a method of producing carveol and dihydrocarveol from piperitone.
(2) Description of the Prior Art
Zukerman studied the effect of auto-oxidized limonene on bacteria, but found it was weakly bacteriostatic, was unstable, and lost its bacteriostatic effect on keeping as was discussed in Nature 168: 517 (1951). He never studied carveol nor the fungicidal activity of auto-oxidized limonene. Kurita investigated the fungicidal activity of several components of essential oils in Biol. Chem., 45(4), 945-952, 1981, and found that cineole, anethole, safrole, d-limonene, .alpha.-pinene, .beta.-pinene, camphene, .beta.-myrcene, caryophyllene, .beta.-cymene, .delta.-camphor, benzaldehyde, vanillin, and furfural are NOT FUNGICIDAL while cinnamaldehyde, phenol, perillyl aldehyde, citral, perillyl alcohol, geraniol, citronellol, 1-nonanol, 1-deconal, 1-menthol and borneol have minimal to good fungicidal activity depending on the component tested. He never studied the anti-yeast nor the anti-fungal activity of carveol. Peter Tetenyi et al studied the essential oils obtained from twelve different specimens of Tanacetum vulgare L. and found eight of the twelve oil specimens to be bactericidal in a concentration of 100 ug/ml against 85-90% of nineteen different bacteria and 100% fungicidal against sixteen species of fungi in a concentration of 50 ug/ml. He delineated numerous chemical components in the oils, but he never studied any of those individual components to determine which, if any, had anti-bacterial, anti-yeast, and/or anti-fungal activity as was outlined in Herba Hungarica, 1981, Tom 20, No. 1-2, pages 57-74. In the Botanical Gazette 122, 194-8 (1961), R. C. French showed that carveol stimulates (rather than inhibits) the germination of wheat stem rust uredospores suggesting that carveol promotes the growth of fungi. Knoblock found that the antimicrobial action of essential oils is related to their ability to penetrate the cell membrane of bacteria and fungi as was shown in the Journal of Essential Oil Res. 1989, 1(3), 119-28, but he never demonstrated which components of the es oils, if any, have anti-bacteria, anti-yeast and/or anti-fungal activity. Chastain and Sanders developed a method of making limonene bactericidal and fungicidal as was outlined in U.S. Pat. No.5,153,229, but they never studied carveol for fungicidal activity. Gauvreau showed a means of producing disinfecting compositions in U.S. Pat. No. 3,595,975 by combining cetyl pyridinium with terpenes to form antiseptics. Gauvreau never studied the use of carveol alone nor in combination with cetyl pyridinium. A. Morel revealed the sterilizing action of carveol, dihydrocarveol, and their ozonization products in Comp. Rend. Soc. Biol. Volume 115, pages 536-8 (1934). He demonstrated the bactericidal activity of carveol and dihydrocarveol, but he never studied them for anti-yeast or anti-fungal activity. J. C. Maruzzella and L. Liguori reported the in vitro anti-fungal activity of essential oils in the Journal of the American Pharmaceutical Association, Vol. XLVII, No. 4, April 1958, pages 250-4, but they did not study the anti-yeast or the anti-fungal activity of carveol. J. C. Maruzzella and Jerry Balter showed the action of essential oils on phytopathogenic fungi in the Plant Disease Reporter Vol. 43, No. 11, Nov. 1959, pages 1143-1147, but they did not study the anti-yeast or the anti-fungal activity of carveol. D. D. Whitehead in U.S. Pat. No. 3,743,747 showed the fungicidal activity of several oxo-derivatives of limonene and dipentene, but he never studied the fungicidal activity of carveol. J. C. Maruzzella et al reported the action of odoriferous organic chemicals and essential oils on wood-destroying fungi in the Plant Disease Reporter, Vol 44, No. 10 (1960); carveol was not studied. Murdook and Allen showed the germicidal effect of sodium benzoate against yeast is enhanced by orange peel oil and d-limonene (stripper oil), as was reported in Food Technology, Vol 14, No. 9, 1960, pages 441-5. They never studied the action of carveol against yeast or fungi. Kellner et al studied ethereal oils for antimicrobial activity, but they never studied the oils nor any of their chemical constituents for anti-yeast or anti-fungal activity as was outlined in Arzneimittel-Forschung 5, 224-9 (1955).
It should be pointed out that the drugs which are bactericidal are usually not fungicidal, and drugs which are fungicidal are usually not bactericidal. In humans, the use of bactericidal antibiotics frequently promotes the growth of yeast. Table A, which follows, exemplifies the anti-bacterial, anti-yeast and anti-fungal activity of several commonly used anti-bacterial, anti-yeast, and anti-fungal antibiotics.
TABLE A __________________________________________________________________________ ANTIBIOTIC ACTIVITY AGAINST ANTIBIOTICS Gm + Bact Gm - Bact A F Bact Yeast Fungi __________________________________________________________________________ A. ANTIBACTERIAL 1. Ampicillin YES YES NO NO NO 2. Cephalothin YES YES NO NO NO 3. Chloramphenicol YES YES NO NO NO 4. Erythromycin YES NO NO NO NO 5. Ethambutol NO NO YES NO NO 6. Gentamicin YES YES NO NO NO 7. Isoniazid NO NO YES NO NO 8. Nitrofurantoin NO YES NO NO NO 9. Penicillin YES NO NO NO NO 10. Rifampin YES NO YES NO NO 11. Streptomycin YES YES YES NO NO 12. Sulfonamides NO YES NO NO NO 13. Tetracycline YES YES NO NO NO 14. Vancomycin YES YES NO NO NO B. ANTIYEAST 1. Nystatin NO NO NO YES NO 2. Gentian Violet NO NO NO YES NO C. ANTIFUNGAL 1. Chlotrimazole NO NO NO YES YES 2. Griseofulvin NO NO NO NO YES __________________________________________________________________________
Gm+Bact=Gram Positive Bacteria, Gm-Bact=Gram Negative Bacteria, A F Bact=Acid Fast Bacteria, YES=Kills Organism, NO=No Activity Against Organism
It should be noted in the table above that none of the anti-bacterial antibiotics kill yeast nor fungi, and none of the anti-yeast nor anti-fungal antibiotics kill bacteria. Thus an anti-fungal or anti-yeast antibiotic is not expected to kill bacteria, and an anti-bacterial antibiotic is not expected to kill yeast nor fungi. Anti-fungal antibiotics do not necessarily kill yeast, and anti-yeast antibiotics do not necessarily kill fungi.
Several significant differences between yeast and fungi are known and are listed. For instance: (1) a yeast culture can be grown in 24-48 hours while a fungus culture requires 7-14 days to grow. (2) Yeast readily grow on blood agar while fungi grow on sabouraud dextrose agar. (3) The use of anti-bacterial antibiotics in humans promotes the growth of yeast but not fungi. (4) Several anti-yeast antibiotics do not kill fungi and several anti-fungal antibiotics do not kill yeast.